Each year more than 20 percent of the 3.5 million Americans infected with hepatitis C progress to cirrhosis and ten to fifteen thousand develop end-stage liver disease. Because hepatitis C and HIV disease share common modes of transmission, co-infection occurs in 8-10 percent of all HIV-infected individuals overall and is present in over 70 percent of those with parenteral risk factors. There are few data available on the natural history of HIV and HCV co-infection in specific risk groups, as most previous studies have not assessed the impact of confounding variables such as alcohol use, continuing substance abuse, malnutrition, duration of HCV infection, and degree of HIV-related immune suppression. Moreover, current data regarding the impact of HIV on HCV infection are changing rapidly due to the widespread use of highly active antiretroviral therapy (HAART). New cases of HIV and HCV are expected to continue to occur in substance abusers, since HIV infection is increasing rapidly in inner-city populations. The purpose of this study is to examine the natural history of HIV and HCV co-infection in a large inner city cohort who are predominately minority and have a history of polysubstance abuse. We will compare three groups: 1) HIV and HCV infected, 2) HCV infected alone, and 3) HIV infected alone. Epidemiologic studies will be conducted to explore the risk factors associated with HCV progression, morbidity, and mortality, using both standard clinical parameters and novel surrogate markers of liver fibrosis. Additional targeted substudies will examine the important clinical question of whether therapy of either the HCV or HIV disease alters progression of liver disease. Finally, immunologic studies aimed at increasing our understanding of the pathogenesis of liver injury and why it may be accelerated in HIV disease will be performed. The central hypothesis of this proposal is that alterations in immune function associated with HIV infection are the main determinant of poorer hepatitis C outcomes. The specific aims of this grant are: 1) to identify the variable(s) that impact the progression of HCV infection in HIV-infected individuals; 2) to determine the effect of HAART on HCV in dually infected persons; and 3) to define the immunologic variables that predict more rapidly progressive liver disease. These studies are expected to improve our understanding of the natural history and pathogenesis of HCV in immunosuppressed hosts.